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Gastroenteropancreatic endocrine tumors: Effect of Sandostatin® on tumor growth
Gastroenteropancreatic Effect of Sandostatin@ R.Arnold,
R. Benning, C. Neuhaus,
M. Rolwage,
Endocrine on Tumor
M.E. Trautmann,
Tumors: Growth
and the German Sandostatin@
Study Group
One hundred fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumors entered a prospective multicenter trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumors, and five with other endocrine GEP tumors) to determine the efficacy of 200 pg Sandostatina three times a day in the control of tumor growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a “negative” selection of patients included in the trial and suggesting that Sandostatinm cannot prevent disease progress when it is far advanced. In the evaluation of 88 patients monitored for at least 3 months, partial regression was observed in 4.4%. stable disease in 50%. and tumor progression in 45%. However, an initially favorable response frequently occurred with a decrease in response later: 54.4% at 3 months to 38% at 12 months for the whole group of patients. Proven inhibition of tumor growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatina exerts a beneficial effect on tumor growth in patients with metastatic endocrine GEP tumors. This beneficial effect decreases with time and is as yet unpredictable in the individual patient. Copyright 0 1992 by W.B. Saunders Company
M
ENDOCRINE gastroenteropancreatic ALIGNANT (GEP) tumors usually have a slow growth rate; standstill or minimal progression over years and even decades Therefore, measures that do not have been documented.‘-3 cause a deterioration in the quality of the patient’s life, such as palliative surgery by excision of easily resectable tumor mass, should always be considered and may result in longlasting clinical remissions3 Alternatively, hepatic artery embolization4 or chemotherapy”’ reduce elevated plasma hormone levels, improve clinical symptoms, and induce remissions. Response rates have been reported between 20% and 60%, but it is uncertain whether survival is influenced by these strategies.’ Efficacy in most patients is unpredictable, and severe side effects have to be reckoned with if chemotherapy is started. Recently, it has been shown that clinical improvement and tumor remission can be achieved in single cases of metastatic endocrine GEP tumors with interferon alpha’0-‘3 and with the somatostatin analogue Sandostatin@ (SMS 20 l-995, Sandoz, Basel, Switzerland).‘.‘4-22 Despite the mechanism of action of Sandostatin@ being unknown, it shows remarkable antiproliferative activities. 23.24Evidence for this has arisen from in vitro studies on a variety of solid tumors including breast, prostate, lung, colon, and exocrine pancreas cancersz4 It has been suggested that the antiproliferative effect of Sandostatin@ and its beneficial effect on hormone-mediated symptoms, such as flushing and diarrhea in carcinoid syndrome and Verner-Morrison syndrome, are mediated by somatostatin receptors present in large numbers on exocrine
and endocrine tumors.24“6 Since even long-term treatment with Sandostatin@ has remarkably few side effects. it could become the treatment of choice if its antiproliferative effect on malignant endocrine GEP tumors can be documented in prospective studies. The aim of this report is to present first-interim data from a German multicenter trial investigating the effect of 1 year of treatment with a standardized dose of Sandostatin@ on the growth of malignant endocrine GEP tumors. PATIENTS AND METHODS One hundred fifteen patients from 45 centers with endocrine GEP tumors and extensive metastatic disease were enrolled in this oneyear prospective trial; the study sample is described in Table 1. All patients received Sandostatin@ in a dose of 200 pg every 8 hours subcutaneously (SC). According to the study design, treatment was intended to last for at least 12 months, and it was discontinued after 3 to 6 months if patients showed fast tumor progression during treatment; otherwise, Sandostatin@ therapy was continued for as long as patients wished to receive treatment. Tumor growth was assessed at 3-month intervals by abdominal computed tomography. The number of metastases within the liver, hepatoduodenal ligament. or mesenterium, paraortic or elsewhere, was estimated, and the size of several reference metastases was determined by measuring the perpendicular diameters of each metastasis. Progression was defined as an increase in tumor size by more than 25% within 3 months as assessed by the sum of two perpendicular diameters measured in two different metastases. or by the appearance of new metastases. Standstill was assumed if less than a 25% increase or decrease in tumor size was seen within the period. Partial regression was defined as a decrease in tumor size by more than 25% within the observation period. RESULTS
Prom the Department of Internal Medicine, Division of Gastroenteroiogy and Metabolism, and the Department of Radiology, Philipps University, Marburg/Lahn, Germany. Supported by Sandoz. Nuremberg, Germany>. This paper (with virtually the same content) will also publish in a supplement to Digestive Diseases and Sciences (in press), Address reprint requests to R. Arnold, MD, Department ofInternal Medicine, Philipps University, Baldingerstrasse 9, 3550 Marburg/ Lahn. Germany. Copyright 0 1992 b.v W.B. Saunders Company 00260495/92/4109-2012$03.00/O 116
Deaths Of 85 patients already evaluated in the trial, 34 (40%) died, 14 before and 20 after the first follow-up investigation at 3 months (Table 1). This demonstrates that the patients included in the trial represent the whole range of manifestations characteristic of malignant endocrine GEP tumors, ie, patients with a fulminant disease course who are unresponsive to any treatment and who die within a few weeks or months, and long-lasting courses reflecting the slow growth rate of the Merabolism. Vol 41,
No 9, Suppl 2
(September), 1992:
pp
1 16-l
18
EFFECT OF SANDOSTATINB
117
ON TUMOR GROWTH
Table 1. Gastrinoma
Study Sample
Carcinoid Syndrome
-
-
Nonfunctionww
Tumors
Other Tumors
Total
12
53
45
5
1
20
7
2
30
11
33
38
3
85
6
19
16
1
Due to death
3
7
10
Due to progression
1
1
1
Entered the study Still under rnvestigation Fully evaluated Completed 12 months
115
Drop-out after first follow-up 2
1
Due to other reasons Drop-out hefore first follow-up 1
Due to death Due to other reasons
5
8
14
1
2
3
majority of endocrine GEP tumors. The high death rate of this study sample, with most deaths occurring within the first 3 months, indicates that more patients with exploding tumor growth behavior were included than would be expected from overall survival rates in malignant endocrine GEP tumors, which suggests a “negative” selection of patients. Effect of SandostatirP on Tumor Growth In the evaluation of 68 patients followed for at least 3 months (Table l), partial regression was observed in three patients (4.4%) stable disease in 34 patients (SO%),and tumor progression in 3 1 patients (45.6%). Malignant gastrinoma and nonfunctioning GEP tumors were more prone to progress during Sandostatin” treatment than tumors leading to carcinoid syndrome. Hormone suppression during Sandostatin@ treatment of 50% over 3 months and longer has been observed in 18 of 38 patients evaluated so far. There was a remarkable parallel between tumor growth behavior and hormone secretion; tumor progression, ie, failure of Sandostatin@, was mostly paralleled by the absence of inhibition of hormone suppression. By contrast, partial regression and standstill of tumor growth during Sandostatin@ treatment was mirrored by concomitant hormone suppression in all but one patient. Duration of Tumor Growth Inhibition During 1 Year of Treatment With SandostatirP Forty-one of 68 patients have been monitored for at least 12 months. The overall response rate of these patients when investigated at 3 months was 54.4%; after 12 months the response rate decreased to 38%. DISCUSSION
The main purpose of this study was the prospective investigation of the antiproliferative effect of Sandostatin@, as it has been suggested from previous case reports’*‘4-22in unselected patients with malignant endocrine GEP tumors. One
hundred fifteen patients were included in the trial, of which 85 have been finally evaluated in this report. The death rate of 40%. with many deaths occurring before the first followup investigation at 3 months, can only be explained by an unexpectedly high percentage of patients with advanced disease who had failed to respond to other therapeutic strategies, such as chemotherapy and interferon alpha, before undergoing Sandostatin@ treatment. The inclusion of these patients in the trial avoided a “favorable” patient selection. It must be stressed that this high percentage of deaths within a relatively short observation period of 1 to 2 years is uncommon for malignant endocrine GEP tumors. The success rate of a specific, antiproliferative, therapeutic strategy must therefore be biased by an unexpectedly high percentage of patients with the disease in its final stage, as was included in this study sample. Response rates have therefore been separately calculated for a subgroup of 68 patients monitored for at least 3 months and 4 1 of these for 12 months. For the 85 patients taken as a whole, it can be concluded that Sandostatin@ does not prevent progress of the disease when it is in a far advanced stage. In the subgroup of 68 patients, an overall response rate to Sandostatin@ of 54.0% was observed. with partial regression in 4.4% and stable disease in 50%. This favorable response to Sandostatin@ is paralleled by a suppression in serum and urinary hormone parameters, whereas in most patients with tumor progression, Sandostatin@ failed to suppress hormone secretion by more than 50%. This trial gives only an insufficient answer to the question of which patients with malignant endocrine GEP tumors would profit from treatment with Sandostatin@. We demonstrated that suppression of hormone release was paralleled by inhibition of tumor growth. We are confident that the final evaluation of the German multicenter trial will provide at least a partial answer to the important question of whether the beneficial effect of Sandostatin@ on tumor growth can perhaps be predicted from additional variables as yet not evaluated.
REFERENCES
1. Arnold R, Neuhaus C, Benning R, et al: Somatostatin Sandostatin and inhibition of tumour growth in patients astatic endocrine gastro-entero-pancreatic (CEP)-tumours.
analogue with metWorld J
Surg (in press)
2. Arnold R: Therapeutic strategies in the management crine GEP-tumours. Eur J Clin Invest 20:82-90. 1990
of endo-
3. Creutzfeldt W: Endocrine tumours of the pancreas, in Arquilla E, Volks BW (eds): The Diabetic Pancreas (ed. 2). New York. NY. Plenum, 1985. pp 543-561 4. Allison DJ, Jordan H, Hennessy 0: Therapeutic embolisation of the hepatic artery: A review of 75 procedures. Lancet 1:595-599, 1985
118
5. Moertel CC. Hanley JA: Combination chemotherapy trials in metastatic carcinoid tumour and the malignant carcinoid syndrome. Cancer Clin Trials 2:327-334, 1979 6. Moertel CC, Hanley JA, Johnson LA: Streptozotocin alone compared with streptozotocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 303: 1189-l 194, 1980 7. Engstrom PF, Lavin PT. Folsch E, et al: Streptozotocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumour. J Clin Oncol 2:1255-1259, 1984 8. Kvols LK. Buck M, Moertel CG. et al: Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 107:162-168, 1987 9. von Schrenk T, Howard JM, Doppman JHL. et al: Prospective study of chemotherapy in patients with metastatic gastrinoma. Gastroenterology 94: 1326-I 334. 1988 10. Oberg K, Funa K. Alm G: Effects of leucocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid turnouts and carcinoid syndrome. N Engl J Med 309: I29133, 1983 Il. Eriksson B, Oberg K. Alm G, et al: Treatment of malignant endocrine pancreatic tumours with human leucocyte interferon. Lancet 2: I307- 1309, 1986 12. Smith DB, Scarffe JH, Wagstaff J, et al: Phase II trial of rDNA alfa 2b interferon in patients with malignant carcinoid tumour. Cancer Treat Rep 711265-1266, 1987 13. Hassen LE. Schrampf E, Kolbenstredt AN, et al: Recombinant alpha-2 interferon with or without hepatic artery embolisation in the treatment of mid-gut carcinoid tumours-A preliminary report. Acta Oncol 28:439-443, 1989 14. Kraenzlin ME, Ch’ng JLC, Wood SM, et al: Long term treatment of a VIPoma with somatostatin analogue resulting in remission of symptoms and possible shrinkage of metastases. Gastroenterology 88:185-187. 1985 15. Sagman U, Sheldon F: Demonstration of tumour regression with somatostatin analogue (SMS 201-995) in a patient with pan-
ARNOLD ET AL
creatic cholera. Sixth International Symposium on Gastrointestinal Hormones, Vancouver, Canada, July 6-10. 1986 16. Kvols LK, Moertel CG, O’Connell M, et al: Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 3 17:162- 168. 1987 17. Wiedenmann B, Rath U, Radsch R, et al: Tumour regression of an ileal carcinoid under the treatment with the somatostatin analogue SMS 201-995. Klin Wochenschr 66:75-77. 1988 18. Vinik A, Moattari AR: Use of somatostatin analogue in management of carcinoid syndrome. Dig Dis Sci 34: 14.S27S, 1989 (suppl) 19. Maton PN, Gardener JD, Jensen RT: Use of long-acting somatostatin analogue SMS 201-995 in patients with pancreatic islet cell tumours. Dig Dis Sci 34:285-395. 1989 (suppl) 20. Gordon P: Somatostatin and somatostatin analogue (SMS 20 I 995) in treatment of hormone secreting tumours of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. (NIH conference). Ann Intern Med 110:35-50, 1989 2 I. Mozell EM, Weltering EA. O’Dorisio TM, et al: Effect of somatostatin analogue on peptide release and tumour growth in the Zollinger-Ellison syndrome. Surgery 170:476-484. 1990 22. Creutzfeldt W, Bartsch HH, Jacubaschke U, et al: Treatment of gastrointestinal endocrine tumours with interferon-alpha and octreotide. Acta Oncol 30:529-535. 199I 23. Cai RZ, Szoke B, Lu R. et al: Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. Proc Nat1 Acad Sci USA 83:1986-1990. 1986 24. Evers BM, Parekh D, Townsend CM, et al: Somatostatin and analogues in the treatment of cancer: A review. Ann Surg 2 13:190198, 1991 25. Reubi JC, Hacki WH, Lamberts SWJ: Hormone-producing gastrointestinal tumours contain a high density of somatostatin receptors. J Clin Endocrinol Metab 65: 1127- 1134. 1987 26. Sato GH, Sato JD: Growth factor receptor monoclonal antibodies and cancer immunotherapy. JNCI 8 1:I600- 1601, I989 (editorial)
R. Benning, C. Neuhaus,
M. Rolwage,
Endocrine on Tumor
M.E. Trautmann,
Tumors: Growth
and the German Sandostatin@
Study Group
One hundred fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumors entered a prospective multicenter trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumors, and five with other endocrine GEP tumors) to determine the efficacy of 200 pg Sandostatina three times a day in the control of tumor growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a “negative” selection of patients included in the trial and suggesting that Sandostatinm cannot prevent disease progress when it is far advanced. In the evaluation of 88 patients monitored for at least 3 months, partial regression was observed in 4.4%. stable disease in 50%. and tumor progression in 45%. However, an initially favorable response frequently occurred with a decrease in response later: 54.4% at 3 months to 38% at 12 months for the whole group of patients. Proven inhibition of tumor growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatina exerts a beneficial effect on tumor growth in patients with metastatic endocrine GEP tumors. This beneficial effect decreases with time and is as yet unpredictable in the individual patient. Copyright 0 1992 by W.B. Saunders Company
M
ENDOCRINE gastroenteropancreatic ALIGNANT (GEP) tumors usually have a slow growth rate; standstill or minimal progression over years and even decades Therefore, measures that do not have been documented.‘-3 cause a deterioration in the quality of the patient’s life, such as palliative surgery by excision of easily resectable tumor mass, should always be considered and may result in longlasting clinical remissions3 Alternatively, hepatic artery embolization4 or chemotherapy”’ reduce elevated plasma hormone levels, improve clinical symptoms, and induce remissions. Response rates have been reported between 20% and 60%, but it is uncertain whether survival is influenced by these strategies.’ Efficacy in most patients is unpredictable, and severe side effects have to be reckoned with if chemotherapy is started. Recently, it has been shown that clinical improvement and tumor remission can be achieved in single cases of metastatic endocrine GEP tumors with interferon alpha’0-‘3 and with the somatostatin analogue Sandostatin@ (SMS 20 l-995, Sandoz, Basel, Switzerland).‘.‘4-22 Despite the mechanism of action of Sandostatin@ being unknown, it shows remarkable antiproliferative activities. 23.24Evidence for this has arisen from in vitro studies on a variety of solid tumors including breast, prostate, lung, colon, and exocrine pancreas cancersz4 It has been suggested that the antiproliferative effect of Sandostatin@ and its beneficial effect on hormone-mediated symptoms, such as flushing and diarrhea in carcinoid syndrome and Verner-Morrison syndrome, are mediated by somatostatin receptors present in large numbers on exocrine
and endocrine tumors.24“6 Since even long-term treatment with Sandostatin@ has remarkably few side effects. it could become the treatment of choice if its antiproliferative effect on malignant endocrine GEP tumors can be documented in prospective studies. The aim of this report is to present first-interim data from a German multicenter trial investigating the effect of 1 year of treatment with a standardized dose of Sandostatin@ on the growth of malignant endocrine GEP tumors. PATIENTS AND METHODS One hundred fifteen patients from 45 centers with endocrine GEP tumors and extensive metastatic disease were enrolled in this oneyear prospective trial; the study sample is described in Table 1. All patients received Sandostatin@ in a dose of 200 pg every 8 hours subcutaneously (SC). According to the study design, treatment was intended to last for at least 12 months, and it was discontinued after 3 to 6 months if patients showed fast tumor progression during treatment; otherwise, Sandostatin@ therapy was continued for as long as patients wished to receive treatment. Tumor growth was assessed at 3-month intervals by abdominal computed tomography. The number of metastases within the liver, hepatoduodenal ligament. or mesenterium, paraortic or elsewhere, was estimated, and the size of several reference metastases was determined by measuring the perpendicular diameters of each metastasis. Progression was defined as an increase in tumor size by more than 25% within 3 months as assessed by the sum of two perpendicular diameters measured in two different metastases. or by the appearance of new metastases. Standstill was assumed if less than a 25% increase or decrease in tumor size was seen within the period. Partial regression was defined as a decrease in tumor size by more than 25% within the observation period. RESULTS
Prom the Department of Internal Medicine, Division of Gastroenteroiogy and Metabolism, and the Department of Radiology, Philipps University, Marburg/Lahn, Germany. Supported by Sandoz. Nuremberg, Germany>. This paper (with virtually the same content) will also publish in a supplement to Digestive Diseases and Sciences (in press), Address reprint requests to R. Arnold, MD, Department ofInternal Medicine, Philipps University, Baldingerstrasse 9, 3550 Marburg/ Lahn. Germany. Copyright 0 1992 b.v W.B. Saunders Company 00260495/92/4109-2012$03.00/O 116
Deaths Of 85 patients already evaluated in the trial, 34 (40%) died, 14 before and 20 after the first follow-up investigation at 3 months (Table 1). This demonstrates that the patients included in the trial represent the whole range of manifestations characteristic of malignant endocrine GEP tumors, ie, patients with a fulminant disease course who are unresponsive to any treatment and who die within a few weeks or months, and long-lasting courses reflecting the slow growth rate of the Merabolism. Vol 41,
No 9, Suppl 2
(September), 1992:
pp
1 16-l
18
EFFECT OF SANDOSTATINB
117
ON TUMOR GROWTH
Table 1. Gastrinoma
Study Sample
Carcinoid Syndrome
-
-
Nonfunctionww
Tumors
Other Tumors
Total
12
53
45
5
1
20
7
2
30
11
33
38
3
85
6
19
16
1
Due to death
3
7
10
Due to progression
1
1
1
Entered the study Still under rnvestigation Fully evaluated Completed 12 months
115
Drop-out after first follow-up 2
1
Due to other reasons Drop-out hefore first follow-up 1
Due to death Due to other reasons
5
8
14
1
2
3
majority of endocrine GEP tumors. The high death rate of this study sample, with most deaths occurring within the first 3 months, indicates that more patients with exploding tumor growth behavior were included than would be expected from overall survival rates in malignant endocrine GEP tumors, which suggests a “negative” selection of patients. Effect of SandostatirP on Tumor Growth In the evaluation of 68 patients followed for at least 3 months (Table l), partial regression was observed in three patients (4.4%) stable disease in 34 patients (SO%),and tumor progression in 3 1 patients (45.6%). Malignant gastrinoma and nonfunctioning GEP tumors were more prone to progress during Sandostatin” treatment than tumors leading to carcinoid syndrome. Hormone suppression during Sandostatin@ treatment of 50% over 3 months and longer has been observed in 18 of 38 patients evaluated so far. There was a remarkable parallel between tumor growth behavior and hormone secretion; tumor progression, ie, failure of Sandostatin@, was mostly paralleled by the absence of inhibition of hormone suppression. By contrast, partial regression and standstill of tumor growth during Sandostatin@ treatment was mirrored by concomitant hormone suppression in all but one patient. Duration of Tumor Growth Inhibition During 1 Year of Treatment With SandostatirP Forty-one of 68 patients have been monitored for at least 12 months. The overall response rate of these patients when investigated at 3 months was 54.4%; after 12 months the response rate decreased to 38%. DISCUSSION
The main purpose of this study was the prospective investigation of the antiproliferative effect of Sandostatin@, as it has been suggested from previous case reports’*‘4-22in unselected patients with malignant endocrine GEP tumors. One
hundred fifteen patients were included in the trial, of which 85 have been finally evaluated in this report. The death rate of 40%. with many deaths occurring before the first followup investigation at 3 months, can only be explained by an unexpectedly high percentage of patients with advanced disease who had failed to respond to other therapeutic strategies, such as chemotherapy and interferon alpha, before undergoing Sandostatin@ treatment. The inclusion of these patients in the trial avoided a “favorable” patient selection. It must be stressed that this high percentage of deaths within a relatively short observation period of 1 to 2 years is uncommon for malignant endocrine GEP tumors. The success rate of a specific, antiproliferative, therapeutic strategy must therefore be biased by an unexpectedly high percentage of patients with the disease in its final stage, as was included in this study sample. Response rates have therefore been separately calculated for a subgroup of 68 patients monitored for at least 3 months and 4 1 of these for 12 months. For the 85 patients taken as a whole, it can be concluded that Sandostatin@ does not prevent progress of the disease when it is in a far advanced stage. In the subgroup of 68 patients, an overall response rate to Sandostatin@ of 54.0% was observed. with partial regression in 4.4% and stable disease in 50%. This favorable response to Sandostatin@ is paralleled by a suppression in serum and urinary hormone parameters, whereas in most patients with tumor progression, Sandostatin@ failed to suppress hormone secretion by more than 50%. This trial gives only an insufficient answer to the question of which patients with malignant endocrine GEP tumors would profit from treatment with Sandostatin@. We demonstrated that suppression of hormone release was paralleled by inhibition of tumor growth. We are confident that the final evaluation of the German multicenter trial will provide at least a partial answer to the important question of whether the beneficial effect of Sandostatin@ on tumor growth can perhaps be predicted from additional variables as yet not evaluated.
REFERENCES
1. Arnold R, Neuhaus C, Benning R, et al: Somatostatin Sandostatin and inhibition of tumour growth in patients astatic endocrine gastro-entero-pancreatic (CEP)-tumours.
analogue with metWorld J
Surg (in press)
2. Arnold R: Therapeutic strategies in the management crine GEP-tumours. Eur J Clin Invest 20:82-90. 1990
of endo-
3. Creutzfeldt W: Endocrine tumours of the pancreas, in Arquilla E, Volks BW (eds): The Diabetic Pancreas (ed. 2). New York. NY. Plenum, 1985. pp 543-561 4. Allison DJ, Jordan H, Hennessy 0: Therapeutic embolisation of the hepatic artery: A review of 75 procedures. Lancet 1:595-599, 1985
118
5. Moertel CC. Hanley JA: Combination chemotherapy trials in metastatic carcinoid tumour and the malignant carcinoid syndrome. Cancer Clin Trials 2:327-334, 1979 6. Moertel CC, Hanley JA, Johnson LA: Streptozotocin alone compared with streptozotocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 303: 1189-l 194, 1980 7. Engstrom PF, Lavin PT. Folsch E, et al: Streptozotocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumour. J Clin Oncol 2:1255-1259, 1984 8. Kvols LK. Buck M, Moertel CG. et al: Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 107:162-168, 1987 9. von Schrenk T, Howard JM, Doppman JHL. et al: Prospective study of chemotherapy in patients with metastatic gastrinoma. Gastroenterology 94: 1326-I 334. 1988 10. Oberg K, Funa K. Alm G: Effects of leucocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid turnouts and carcinoid syndrome. N Engl J Med 309: I29133, 1983 Il. Eriksson B, Oberg K. Alm G, et al: Treatment of malignant endocrine pancreatic tumours with human leucocyte interferon. Lancet 2: I307- 1309, 1986 12. Smith DB, Scarffe JH, Wagstaff J, et al: Phase II trial of rDNA alfa 2b interferon in patients with malignant carcinoid tumour. Cancer Treat Rep 711265-1266, 1987 13. Hassen LE. Schrampf E, Kolbenstredt AN, et al: Recombinant alpha-2 interferon with or without hepatic artery embolisation in the treatment of mid-gut carcinoid tumours-A preliminary report. Acta Oncol 28:439-443, 1989 14. Kraenzlin ME, Ch’ng JLC, Wood SM, et al: Long term treatment of a VIPoma with somatostatin analogue resulting in remission of symptoms and possible shrinkage of metastases. Gastroenterology 88:185-187. 1985 15. Sagman U, Sheldon F: Demonstration of tumour regression with somatostatin analogue (SMS 201-995) in a patient with pan-
ARNOLD ET AL
creatic cholera. Sixth International Symposium on Gastrointestinal Hormones, Vancouver, Canada, July 6-10. 1986 16. Kvols LK, Moertel CG, O’Connell M, et al: Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 3 17:162- 168. 1987 17. Wiedenmann B, Rath U, Radsch R, et al: Tumour regression of an ileal carcinoid under the treatment with the somatostatin analogue SMS 201-995. Klin Wochenschr 66:75-77. 1988 18. Vinik A, Moattari AR: Use of somatostatin analogue in management of carcinoid syndrome. Dig Dis Sci 34: 14.S27S, 1989 (suppl) 19. Maton PN, Gardener JD, Jensen RT: Use of long-acting somatostatin analogue SMS 201-995 in patients with pancreatic islet cell tumours. Dig Dis Sci 34:285-395. 1989 (suppl) 20. Gordon P: Somatostatin and somatostatin analogue (SMS 20 I 995) in treatment of hormone secreting tumours of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. (NIH conference). Ann Intern Med 110:35-50, 1989 2 I. Mozell EM, Weltering EA. O’Dorisio TM, et al: Effect of somatostatin analogue on peptide release and tumour growth in the Zollinger-Ellison syndrome. Surgery 170:476-484. 1990 22. Creutzfeldt W, Bartsch HH, Jacubaschke U, et al: Treatment of gastrointestinal endocrine tumours with interferon-alpha and octreotide. Acta Oncol 30:529-535. 199I 23. Cai RZ, Szoke B, Lu R. et al: Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. Proc Nat1 Acad Sci USA 83:1986-1990. 1986 24. Evers BM, Parekh D, Townsend CM, et al: Somatostatin and analogues in the treatment of cancer: A review. Ann Surg 2 13:190198, 1991 25. Reubi JC, Hacki WH, Lamberts SWJ: Hormone-producing gastrointestinal tumours contain a high density of somatostatin receptors. J Clin Endocrinol Metab 65: 1127- 1134. 1987 26. Sato GH, Sato JD: Growth factor receptor monoclonal antibodies and cancer immunotherapy. JNCI 8 1:I600- 1601, I989 (editorial)